Tandem pummerer/mannich cyclization cascade of α-sulfinylamides as a method to prepare aza-heterocycles

Article abstract of DOI:10.1021/jo020083x

A series of α-sulfinylenamides was conveniently prepared by the condensation of a primary amine with a ketone, followed by reaction of the resulting imine with ethylsulfenylacetyl chloride and subsequent oxidation with sodium periodate. When treated with p-TsOH, cyclization occurred to produce fused isoquinoline lactams by a mechanism that involves an initial Pummerer reaction followed by a subsequent cyclization of the resulting N-acyliminium ion onto the tethered aromatic ring. The isolation of a single diastereomer was rationalized in terms of a Nazarov-type 4π-electrocyclic reaction followed by π-cyclization onto the least hindered side of the N-acyliminium ion. Another method that was used to generate the α-acylthionium ion intermediate involved the reaction of bis(ethylsulfenylacetyl)acetamides with dimethyl(methyl)thiosulfonium tetrafluoroborate (DMTSF). Treatment of several bis-ethylsulfenylenamides with DMTSF delivered novel spiroheterocycles as single diastereomers in good yield by a related process. The convergency and stereochemical control associated with this cascade sequence make it particularly suited for the assembly of natural product scaffolds. Some preliminary studies were directed toward both mesembrine and deethylibophyllidine. When the model Z-enamido sulfoxide 33 was heated with p-TsOH, a 80% yield of tosylate 34 was obtained as a single diastereomer. In this case, the carbocation intermediate derived from cyclization onto the terminal π-bond was trapped with p-TsOH from the least hindered face, opposite the angular carbomethoxy and methyl groups. Related cyclization cascades were also found to occur with systems containing tethered indole rings.

Full text of DOI:10.1021/jo020083x

Ta n d em P u m m er er /Ma n n ich Cycliza tion Ca sca d e of
r-Su lfin yla m id es a s a Meth od To P r ep a r e Aza -Heter ocycles‡
Albert Padwa,* Todd M. Heidelbaugh, J effrey T. Kuethe, Michael S. McClure, and Qiu Wang
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received February 4, 2002
A series of R-sulfinylenamides was conveniently prepared by the condensation of a primary amine
with a ketone, followed by reaction of the resulting imine with ethylsulfenylacetyl chloride and
subsequent oxidation with sodium periodate. When treated with p-TsOH, cyclization occurred to
produce fused isoquinoline lactams by a mechanism that involves an initial Pummerer reaction
followed by a subsequent cyclization of the resulting N-acyliminium ion onto the tethered aromatic
ring. The isolation of a single diastereomer was rationalized in terms of a Nazarov-type
4π-electrocyclic reaction followed by π-cyclization onto the least hindered side of the N-acyliminium
ion. Another method that was used to generate the R-acylthionium ion intermediate involved the
reaction of bis(ethylsulfenylacetyl)acetamides with dimethyl(methyl)thiosulfonium tetrafluoroborate
(DMTSF). Treatment of several bis-ethylsulfenylenamides with DMTSF delivered novel spiro-
heterocycles as single diastereomers in good yield by a related process. The convergency and
stereochemical control associated with this cascade sequence make it particularly suited for the
assembly of natural product scaffolds. Some preliminary studies were directed toward both
mesembrine and deethylibophyllidine. When the model Z-enamido sulfoxide 33 was heated with
p-TsOH, a 80% yield of tosylate 34 was obtained as a single diastereomer. In this case, the
carbocation intermediate derived from cyclization onto the terminal π-bond was trapped with
p-TsOH from the least hindered face, opposite the angular carbomethoxy and methyl groups. Related
cyclization cascades were also found to occur with systems containing tethered indole rings.
Nitrogen-containing heterocycles are abundant in na-
ture and exhibit diverse and important biological proper-
ties.1,2 Accordingly, novel strategies for the stereoselective
synthesis of azapolycyclic ring systems continue to
receive considerable attention in the field of synthetic
organic chemistry.3-9 A variety of preparative methods
have been developed, and many reviews, monographs,
and reports have been released.1 The elaboration of ring-
fused heterocycles based upon tandem cyclizations are
among the most powerful strategic tools available to the
synthetic organic chemist, because they rapidly increase
the complexity of a substrate while at the same time
making economical use of available functional groups.10-21
‡ This paper is dedicated to Waldemar Adam on the occasion of
his 65th birthday, for his significant contributions to the field of
mechanistic organic chemistry.
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10.1021/jo020083x CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/20/2002
5928
J . Org. Chem. 2002, 67, 5928-5937

Tandem Pummerer/ Mannich Cyclization Cascade
SCHEME 1
Tandem cationic reactions are featured in the biosyn-
thesis of important natural products, and synthetic appli-
cations of both biomimetic and nonbiomimetic tandem
cationic reactions22 have been widely developed. The reac-
tion or N-acyliminium ions with tethered π-bonds rep-
resents one of the most important methods for preparing
complex nitrogen heterocycles.23-26 In recent years, the
Pummerer reaction followed by a π-cyclization has also
been found to be a very effective and general method for
the preparation of many diverse azapolycyclic skele-
tons.27-29 The combination of a Pummerer/Mannich ion
cyclization sequence offers unique opportunities for the
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communication we described a route to various azapoly-
cyclic systems that involved the tandem thionium/
N-acyliminium ion cyclization cascade depicted in
Scheme 1.32
Application of this tandem sequence to alkaloid syn-
thesis is potentially very broad. Among the great variety
of skeletal types of monoterpenoid indole alkaloids, the
ibophyllidene alkaloids are characterized structurally by
the presence of a 2,3,3-trisubstituted indole.33 The pen-
tacyclic pyrrolizino[1,7-cd]carbazole unit present consti-
tutes the core of this intriguing family of natural prod-
ucts.34 We came to recognize that the cascade sequence
outlined in Scheme 1 could possibly be used for a concise
and stereocontrolled synthesis of deethylibophyllidine
(5).35 The retrosynthetic analysis is outlined in Scheme
2. The key step in our plan involves the acid-catalyzed
cyclization of indole 8 into 7. The stereochemical outcome
of this cyclization is assumed to proceed by a syn delivery
of the nucleophilic tether to the initially formed N-
acyliminium ion. Raney nickel desulfurization followed
by amide reduction should deliver 6, which had already
been converted to deethylibophyllidene (5) by Bonjoch
and co-workers.36 In this paper, we report an account of
our efforts dealing with this unique tandem cyclization
sequence.
Resu lts a n d Discu ssion
The strategy delineated in Scheme 2 for the synthesis
of deethylibophyllidene (5) relies on a tandem Pummerer/
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J . Org. Chem. 1998, 63, 6778. See earlier work cited in ref 30 for
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J . Org. Chem, Vol. 67, No. 17, 2002 5929

Padwa et al.
SCHEME 2
SCHEME 3
Mannich cyclization cascade.37 To pursue this approach,
we decided it was necessary to first probe several issues
related to the following questions: (1) will R-sulfin-
ylenamides of type 1 undergo ready 5-ring cyclization,
(2) what is the propensity for the indole π-bond to cyclize
onto the resulting N-acyliminium ion, (3) will the cy-
clization proceed in a stereoselective manner, and (4) how
easy will it be to remove the ethylthio group from the
resulting lactam. Our initial foray into this tandem
cyclization chemistry involved substrates 9 and 12. These
compounds were conveniently prepared in 60-80% yield
from the condensation of 3,4-dimethoxyphenethylamine
with the appropriate aldehyde or ketone followed by
reaction of the resulting imine with ethylsulfenylacetyl
chloride38 and subsequent NaIO4 oxidation. The olefin
geometry was assigned on the basis of NOE studies. In
the case of 9, irradiation of the methyl singlet at δ 1.88
enhanced (8%) the other methyl singlet at δ 1.96.
Treatment of 9 with 2 equiv of p-TsOH in refluxing
benzene afforded 10 in 78% yield (Scheme 3). It is
important to note that only one of several possible
diastereomers of the fused isoquinoline lactam 10 was
observed under the reaction conditions, as indicated by
1H and 13C NMR spectral data (vide infra). The stereo-
chemical assignment was unequivocally established by
X-ray crystallographic analysis, which revealed a syn
relationship between the ethylthio, carbethoxy, and
methyl groups.39 Interestingly, when 9 was treated with
acetic anhydride (10 equiv) in refluxing toluene that
contained a catalytic amount of p-TsOH, the only product
isolated corresponded to the terminally substituted ena-
mide 11. Further heating of 11 in the presence of 2 equiv
of p-TsOH afforded 10 in 78% yield. In the presence of
excess acetic anhydride, the initially formed N-acylimin-
ium ion derived from 9 prefers to undergo deprotonation
rather than cyclization.
R-Sulfinylenamide 12 underwent an analogous cycliza-
tion, affording the fused isoquinoline lactam 13 in 69%
yield. The olefin geometry in 12 rests on the absence of
a NOE between the vinylic hydrogen and the methyl
group. This cyclization reaction also proceeded with high
diastereospecificity and led to a single diastereomer
where the methyl and ethylthio groups are on the same
side of the ring. The NOE enhancement between the
tertiary hydrogen adjacent to the nitrogen atom of the
lactam ring and the vicinal methyl group further defines
the stereochemical relationship of the substituent groups
present in 13.
A plausible mechanism that nicely rationalizes the
stereochemical results involves initial formation of an
R-acylthionium ion (i.e., 14) followed by a Nazarov-type40
4π-electrocyclic ring closure, which occurs in a conrota-
tory fashion to give N-acyliminium ion 15 (Scheme 4).
The final cyclization step proceeds in a stereoselective
manner by attack of the proximal aromatic ring from the
less hindered side of the iminium ion framework.
A rather interesting rearrangement was encountered
when a monosubstituted enamide (i.e., 16) was used.
Subjection of 16 to the acidic conditions resulted in the
formation of 2H-benzo[c]azocin-3-one 19 as the only
isolable product in 42% yield (Scheme 5). More than
likely, the thionium/N-acyliminium ion cascade first
produces tetrahydropyrrolo[2,1-a]isoindol-3-one 17 as a
transient intermediate. Under the reaction conditions the
tricyclic amide undergoes an acid-catalyzed ring opening
to give 18, which is subsequently isomerized to give the
thermodynamically more stable 2H-benzoazocinone 19.
Another method that has occasionally been used to
generate R-acylthionium ions involves the reaction of
thioketals with dimethyl(methylthio)sulfonium tetrafluo-
(37) Padwa, A. J . Chem. Soc., Chem. Commun. 1998, 1417.
(38) Mooradian, A.; Cavallito, C. J .; Bergman, A. J .; Lawson, E. J .;
Suter, C. M. J . Am. Chem. Soc. 1949, 71, 3372.
(39) The authors have deposited coordinates for stuctures 10, 34,
and 38 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, B2 1EZ,
UK.
(40) Denmark, S. E. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 751-
784.
5930 J . Org. Chem., Vol. 67, No. 17, 2002

Tandem Pummerer/ Mannich Cyclization Cascade
SCHEME 4
SCHEME 7
SCHEME 8
SCHEME 5
SCHEME 6
As illustrated in Scheme 7, the cyclization of enamide
22 furnished isoquinolinone 23 in 65% yield. Because all
of the previous examples involved aromatic π-bond cy-
clizations, we decided to study several systems that
possess a simple olefinic tether. We found that treatment
of the cyclohexenyl substituted enamide 24 with p-TsOH
also caused a thionium ion induced Mannich reaction to
occur, ultimately producing 25 in 58% yield.
Attention was next turned to the acid-induced cycliza-
tion of enamides 26 and 31 where the point of attachment
of the interacting π-bond was switched from nitrogen to
carbon. Treatment of 26 with p-TsOH under identical
conditions used for the cyclization of 9 gave 27 as a single
diastereomer in 79% yield (Scheme 8). The ethylthio
group of 27 was reductively cleaved with Raney nickel
to afford lactam 28 in 98% yield. Heating a sample of 27
with Lawesson’s reagent furnished thioamide 29 in 86%
yield, which, in one-step, gave indacene 30 (70%) upon
treatment with Raney nickel. The well-documented
reactivity of allyl silanes toward electrophiles45 suggested
roborate (DMTSF).41,42 This reagent exhibits a remark-
able high reactivity toward thioketals and causes the
carbon-sulfur bond to become labile upon methylthio-
lation.43,44 The initially formed alkylthiosulfonium ion
easily dissociates to produce a thionium ion and ethyl
methyl disulfide. Indeed, we found that the reaction of
bis(ethylsulfenyl)acetamide 20 with DMTSF afforded
isoquinolinone 21 in 82% yield (Scheme 6).
Several types of R-sulfinylenamides were examined so
as to establish the scope and generality of the process.
(41) Trost, B. M.; Murayama, E. J . Am. Chem. Soc. 1981, 103, 6529.
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J . Org. Chem, Vol. 67, No. 17, 2002 5931

Padwa et al.
SCHEME 9
SCHEME 10
that the acid-promoted reaction of sulfinylenamide 31
should provide access to a bicyclic lactam. Indeed, treat-
ment of 31 with p-TsOH afforded the cyclized product
32 in 61% yield. We suspect that the initially formed
lactam, which possesses an exocyclic double bond, is
isomerized under the reaction conditions. The structure
and stereochemistry of products 27 and 32 follow from
analysis of their NMR spectroscopic data, and their
formation is perfectly consistent with the tandem thion-
ium/iminium ion cascade sequence outlined in Scheme
4.
lowed by reaction with bis-ethylsulfenylacetyl chloride48
produced enamide 37 in 63% yield. Interestingly, only
the methylene-substituted enamide 37 was formed in this
reaction. The DMSTF cyclization of 37 provided access
to the unusual spiro-heterocycle 38 whose stereochem-
istry was also established by single-crystal X-ray analysis
(Scheme 10).39 When enamide 37 was allowed to stir with
2 equiv of DBU at 25 °C for 12 h, complete isomerization
to the tetrasubstituted alkenes 39 and 40 (1:1 mixture)
occurred in quantitative yield. Silica gel chromatography
easily separated the two geometrical isomers. The olefin
geometry was assigned on the basis of NOE studies. In
the case of 39, irradiation of the methylene protons
enhanced the methyl singlet at δ 2.09. Similarly, irradia-
tion of the vinylic methyl group at δ 2.06 resulted in an
enhancement of the carbomethoxy signal at δ 3.60 for
the E-isomer 40. As we anticipated from the 4π-conro-
tatory mechanism outlined in Scheme 4, cyclization of
each olefin (i.e., 39 and 40) afforded single diastereomers
epimeric at the ethylthio position without any cross
contamination (Scheme 10).
The convergency and stereochemical control associated
with this cascade sequence make it particularly suited
for the assembly of natural product scaffolds. With this
in mind, some preliminary studies were directed toward
mesembrine (36), a well-known member of the Scelectium
class of alkaloids.46 When the model Z-enamido sulfoxide
33 was heated with p-TsOH, an 80% yield of tosylate 34
was obtained as a single diastereomer (Scheme 9). The
stereochemistry of 34 was established by a single-crystal
X-ray analysis,39 and its formation is consistent with the
proposed 4π-electrocyclic ring closure. In this case, the
carbocation intermediate derived from cyclization onto
the terminal π-bond was trapped with tosic acid from the
least hindered face, opposite the angular carbomethoxy
and methyl groups. Reduction of 34 with Na(Hg) followed
by PCC oxidation afforded 35 in 82% overall yield.
Further studies are aimed at extending this model
cascade reaction toward the synthesis of the Sceletium
class of alkaloids.
To further explore the scope and generality of the
tandem cyclization process, we carried out another varia-
tion of the Pummerer initiation reaction using dithioac-
etal-substituted enamides as thionium ion precursors.41
Sequential treatment of benzylamine with 2-benzo[1,3]-
dioxol-5-ylmethyl-3-oxobutyric acid methyl ester47 fol-
Given the success in forming azapolycyclic ring systems
from enamides possessing simple aromatic and olefinic
tethers, it seemed to us that a related cyclization cascade
might also occur with systems containing a tethered
indole ring. This was particularly important for our
planned approach to deethylibophyllidine. To test this
(46) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1997, 62, 1675.
Mori, M.; Kuroda, S.; Zhang, C. S.; Sato, Y. J . Org. Chem. 1997, 62,
3263. Yoshimitsu, T.; Ogasawara, K. Heterocycles 1996, 42, 135.
Nemoto, H.; Tanabe, T.; Fukumoto, K. J . Org. Chem. 1995, 60, 6788.
Yokomatsu, T.; Isawa, H.; Shibuya, S. Tetrahedron Lett. 1992, 33, 6999.
Dalko, P. I.; Brun, V.; Langlois, Y. Tetrahedron Lett. 1998, 39, 8979.
(47) Barry, R. H.; Mattocks, A. M.; Hartung, W. H. J . Am. Chem.
Soc. 1948, 70, 693.
(48) Bellus, D. Helv. Chim. Acta 1975, 58, 2509.
5932 J . Org. Chem., Vol. 67, No. 17, 2002

Tandem Pummerer/ Mannich Cyclization Cascade
SCHEME 11
tams by a mechanism that involves an initial Pummerer
reaction followed by a subsequent cyclization of the
resulting N-acyliminium ion onto the tethered aromatic
ring. The isolation of a single diastereomer can be
rationalized in terms of a Nazarov-type 4π-electrocyclic
reaction followed by π-cyclization onto the least hindered
side of the N-acyliminium ion. The convergency and
stereochemical control associated with this cascade se-
quence make it particularly suited for the assembly of
natural product scaffolds. Further utilization of this
sequence for the stereocontrolled synthesis of several
pyrrolizino[1,7-cd]carbazole alkaloids is under current
investigation.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry nitrogen. Solutions were evaporated
under reduced pressure with a rotary evaporator, and the
residue was chromatographed on a silica gel column using an
ethyl acetate-hexane mixture as the eluent, unless specified
otherwise.
1-[2-(3,4-Dim et h oxyp h en yl)et h yl]-4-et h ylsu lfen yl-3-
m eth yl-2-m eth ylen e-5-oxop yr r olid in e-3-ca r boxylic Acid
Eth yl Ester (11). To a solution containing 0.4 g (4.0 mmol)
of acetic anhydride and 2 mg of p-toluenesulfonic acid in 50
mL of toluene at reflux was added dropwise 0.18 g (0.4 mmol)
of 3-([2-(3,4-dimethoxyphenyl)ethyl]ethylsulfinylacetylamino)-
2-methylbut-2-enoic acid ethyl ester (9) in 2 mL of toluene.
After heating at reflux for 1 h, the reaction mixture was
concentrated under reduced pressure, and the residue was
subjected to silica gel chromatography to give 0.14 g (78%) of
11 as a colorless oil: IR (neat) 1730, 1645, 1517, 1388, and
SCHEME 12
1
1260 cm-1; H NMR (CDCl3, 300 MHz) δ 1.21 (t, 3H, J ) 7.2
possibility, two differently substituted indolyl enamides
(i.e., 42 and 45) were synthesized from the appropriate
ketones. Treatment of 42 with 2 equiv of p-TsOH in
refluxing benzene afforded the crystalline polycycle 43
in 80% yield (Scheme 11). Raney nickel reduction of 43
furnished 44 in quantitative yield. Likewise, treatment
of enamide 45 with DMTSF initiated a clean cyclization
to deliver spirocycle 46 in 69% yield as a single diaste-
reomer. A possible rationale to account for the formation
of 46 involves a facile equilibration of the carbomethoxy-
bearing stereogenic center via tautomerization of the
N-acyliminium ion intermediate prior to the final ring
closure. Alternatively, the direction of conrotatory closure
may be influenced by the presence of the neighboring
carbomethoxy group. Most importantly, these two ex-
amples clearly demonstrate the facility with which the
thionium/iminium ion cascade occurs with enamides
possessing tethered indole rings.
The potential of further employing this methodology
for the synthesis of various ibophyllidene alkaloids
prompted us to carry out a model study to probe the
likelihood of using the cascade sequence for a synthesis
of deethylibophyllidene (5). Initial feasibility studies were
conducted with enamidosulfoxide 47. Gratifyingly, the
reaction of 47 with trifluoroacetic anhydride gave aza-
cycle 48 in 60% yield (Scheme 12). Further application
of this method to deethylibophyllidene and related alka-
loids is currently underway in our laboratories and will
be reported in due course.
Hz); 1.30 (t, 3H, J ) 7.4 Hz), 1.61 (s, 3H), 2.76 (m, 5H), 3.29
(s, 1H), 3.54 (m, 1H), 3.87 (s, 3H), 3.89 (s, 3H), 4.13 (q, 2H, J
) 7.2 Hz), 4.35 (d, 1H, J ) 2.7 Hz), and 4.41 (d, 1H, J ) 2.7
Hz), 6.79 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 14.9, 21.1,
28.1, 31.6, 42.2, 53.2, 54.4, 55.8, 61.5, 85.3, 111.2, 111.8, 120.6,
130.6, 147.7, 148.0, 148.9, 150.0, 170.4, and 171.9. Anal. Calcd
for C21H29NO5S: C, 61.89; H, 7.17; N, 3.44. Found: C, 61.72;
H, 7.03; N, 3.22.
N-Ben zyl-2-eth ylsu lfin yl-N-vin yla ceta m id e (16). To a
2.6 g (0.24 mol) sample of benzylamine at 0 °C was added 1.1
g of acetaldehyde (0.24 mol). The reaction mixture was stirred
at 0 °C for 2 h and at room temperature for 1 h. After this
time, solid potassium hydroxide pellets were added, and the
reaction mixture was allowed to sit overnight. The mixture
was filtered and the solvent was removed under reduced
pressure to leave behind a yellow oil, which was taken up in
5 mL of CH2Cl2. To this solution was added 2.3 g (17 mmol) of
ethylsulfenylacetyl chloride in 50 mL of CH2Cl2 followed by 1
mL of pyridine. The mixture was allowed to stir for 30 min at
0 °C and then at 25 °C for 3.5 h. The solution was concentrated
under reduced pressure and the residue was chromatographed
on a silica gel column to give 1.3 g (48%) of N-benzyl-2-
ethylsulfenyl-N-vinylacetamide as a pale yellow oil, which was
used in the next step without further purification: IR (neat)
1658, 1559, 1566, and 1457 cm-1;1H NMR (CDCl3, 400 MHz)
δ 1.23 (t, 3H, J ) 7.5 Hz), 2.60 (q, 2H, J ) 7.5 Hz), 3.47 (s,
2H), 4.29-4.52 (m, 2H), 4.84 (s, 2H), 6.86 (dd, 1H, J ) 15 and
9.3 Hz), and 7.14-7.30 (m, 5H); 13C NMR (CDCl3, 100 MHz)
δ 14.6, 26.6, 33.4, 45.8, 96.1, 125.8, 126.9, 127.2, 128.7, 129.2,
133.4, 137.1, and 168.6.
To a 0.3 g (1 mmol) sample of the above enamide in 20 mL
of MeOH was added 0.4 g (1.6 mmol) of NaIO4. After stirring
for 3 h at room temperature, the mixture was diluted with
water and extracted with CH2Cl2. The organic layers were
combined, washed with a saturated NaCl solution, and dried
In conclusion, the acid-catalyzed reaction of a series
of R-sulfinylenamides furnished fused isoquinoline lac-
J . Org. Chem, Vol. 67, No. 17, 2002 5933

Padwa et al.
1
with MgSO4. The mixture was concentrated under reduced
pressure and the residue was chromatographed on silica gel
to give 0.25 g (88%) of N-benzyl-2-ethylsulfinyl-N-vinylaceta-
mide (16) as a pale yellow oil: IR (neat) 1624, 1457, 1182, and
colorless oil: IR (neat) 1681, 1610, 1417, and 1247 cm-1; H
NMR (400 MHz, CDCl3) δ 1.26 (t, 3H, J ) 7.2 Hz), 1.51 (s,
3H), 2.02 (dd, 1H, J ) 12.0 and 11.2 Hz), 2.64-2.92 (m, 5H),
3.08 (dt, 1H, J ) 12.4 and 4.4 Hz), 3.73 (dd, 1H, J ) 10.0 and
9.2 Hz), 3.84 (s, 3H), 3.86 (s, 3H), 4.29 (dd, 1H, J ) 13.2 and
6.4 Hz), 6.52 (s, 1H), and 6.55 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.4, 24.9, 27.6, 28.0, 34.5, 42.7, 43.7, 55.8, 56.0, 58.9,
107.5, 111.4, 124.2, 133.8, 147.8, 148.0, and 170.5. Anal. Calcd
for C17H23NO3S: C, 63.52; H, 7.22; N, 4.36. Found: C, 63.45;
H, 7.08; N, 4.31.
1
1019 cm-1; H NMR (CDCl3, 400 MHz) δ 1.37 (t, 3H, J ) 7.6
Hz), 2.74-2.87 (m, 1H), 2.93-3.06 (m, 1H), 3.99 (s, 2H), 4.49-
4.64 (m, 2H), 4.87 (s, 2H), 6.89 (dd, 1H, J ) 15.2 and 9.2 Hz),
and 7.16-7.34 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 6.8, 46.7,
48.7, 55.2, 99.0, 125.8, 127.0, 127.5, 128.9, 129.4, 132.6, 136.2,
and 164.2. Anal. Calcd for C13H17NO2S: C, 62.13; H, 6.82; N,
5.58. Found: C, 62.05; H, 6.78; N, 5.47.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-2-eth ylsu lfin yl-N-(2-
m eth ylp r op en yl)a ceta m id e (22). To 5 mL (30 mmol) of
dimethoxyphenethylamine in a round-bottom flask at 0 °C was
added 2.7 mL (30 mmol) of 2-methyl propionaldehyde. The
solution was allowed to stir for 30 min at 0 °C and at 25 °C
for 1 h. The reaction mixture was filtered over Na2SO4 and
concentrated under reduced pressure to give 5.6 g (80%) of
[2-(3,4-dimethoxyphenyl)ethyl]isobutylideneamine as a pale
yellow oil, which was used in the next step without further
4-Eth ylsu lfen yl-1,6-d ih yd r o-2H-ben zo[c]a zocin -3-on e
(19). To a 0.24 g (0.9 mmol) sample of sulfoxide 16 in 15 mL
of toluene was added 0.9 mL (10 mmol) of acetic anhydride
and 20 mg of p-TsOH. The resulting solution was heated at
reflux for 3 h. The solution was cooled and concentrated under
reduced pressure, and the residue was subjected to silica gel
chromatography to give 0.1 g (42%) of 19 as a pale yellow oil:
IR (neat) 1684, 1559, and 1457 cm-1 1H NMR (CDCl3, 400
;
purification: IR (neat) 1669, 1516, 1465, 1262, and 1030 cm-1
;
MHz) δ 1.35 (t, 3H, J ) 7.2 Hz), 1.65 (brs, 1H), 2.89 (q, 2H, J
) 7.2 Hz), 3.81 (d, 2H, J ) 2.4 Hz), 4.64 (s, 2H), 6.44 (t, 1H, J
) 2 Hz), and 7.22-7.31 (m, 4H); 13C NMR (CDCl3, 100 MHz)
δ 13.9, 25.3, 46.8, 51.5, 127.9, 128.3, 128.6, 128.9, 129.1, 129.7,
136.5, 137.2, and 168.9. Anal. Calcd for C13H15NOS: C, 66.93;
H, 6.49; N, 6.01. Found: C, 6.72; H, 6.34; N, 5.97.
1H NMR (CDCl3, 400 MHz) δ 0.97 (d, 6H, J ) 9.2 Hz), 2.32
(m, 1H), 2.81 (t, 2H, J ) 9.6 Hz), 3.54 (t, 2H, J ) 9.6 Hz), 3.81
(s, 3H), 3.84 (s, 3H), 6.65-6.76 (m, 3H), and 7.35 (d, 1H, J )
6.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 19.5, 34.1, 37.1, 55.9,
59.1, 63.1, 112.3, 112.6, 121.1, 132.8, 147.5, 148.8, and 170.5.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-2-bis(eth ylsu lfen y-
la cetyl)-N-isop r op en yla ceta m id e (20). To a solution of 3,4-
dimethoxyphenethylamine (10 mL, 60 mmol) in benzene (60
mL) was added 6.5 mL (90 mmol) of anhydrous acetone,
followed by 24 g of 4 Å molecular sieves. The reaction mixture
was stirred at room temperature for 24 h before filtering
through a plug of Celite. The plug was rinsed with diethyl
ether, and the combined filtrates were concentrated under
reduced pressure to give 11 g (84%) of 4-(3-aza-4-methylpent-
3-enyl)-1,2-dimethoxybenzene as a yellow oil, which was used
in the next step without further purification: IR (neat) 1659,
1588, 1509, 1253, and 1139 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.62 (s, 3H), 1.92 (s, 3H), 2.81 (t, 2H, J ) 8.0 Hz), 3.71 (t,
2H, J ) 7.6 Hz), 3.76 (s, 3H), 3.78 (s, 3H), and 6.70 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 18.0, 29.0, 36.6, 53.3, 55.4, 55.5,
110.8, 111.9, 120.3, 132.9, 146.9, 148.3, 167.2.
A 2.3 g (16.7 mmol) sample of ethylsulfenyl-acetyl chloride
in 50 mL of CH2Cl2 at 0 °C was added to 2.6 g (11 mmol) of
the above imine, followed by the addition of 1 mL of pyridine
(12 mmol). The mixture was stirred at 0 °C for 30 min and
then at 25 °C for 12 h. The solution was concentrated under
reduced pressure and the residue was chromatographed on
silica gel to give 2.3 g (62%) of N-[2-(3,4-dimethoxyphenyl)-
ethyl]-2-ethylsulfenyl-N-(2-methylpropenyl)acetamide as a pale
yellow oil, which was used in the next step without purifica-
tion: IR (neat) 1644, 1516, 1417, 1146, and 1029 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.23 (t, 3H, J ) 7.2 Hz), 1.59 (d,
3H, J ) 1.6 Hz), 1.71 (d, 3H, J ) 1.6 Hz), 2.60 (q, 2H, J ) 7.2
Hz), 2.75 (t, 2H, J ) 8 Hz), 3.16 (s, 2H), 3.61 (t, 2H, J ) 8 Hz),
3.84 (s, 3H), 3.87 (s, 3H), 5.87 (m, 1H), and 6.74 (m, 3H); 13C
NMR (CDCl3, 100 MHz) δ 14.6, 17.9, 22.1, 26.5, 33.4, 33.5,
49.8, 56.1, 111.3, 112.2, 120.9, 124.1, 131.8, 136.4, 147.7, 149.0,
and 170.1.
To a solution of 0.5 g (2.4 mmol) of the above imine in CH2-
Cl2 (12 mL) was added 0.2 mL (2.4 mmol) of pyridine, followed
by 0.5 g (2.4 mmol) of bis-ethylsulfenylacetyl chloride. The
reaction mixture was stirred at this temperature for 2 h before
quenching with a saturated solution of NaHCO3. The organic
layer was separated and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure and the crude
oil was purified by silica gel chromatography to furnish 0.44
g (65%) of enamide 20 as a colorless oil: IR (neat) 1638, 1510,
To a 2.0 g (6.0 mmol) sample of the above sulfide in 50 mL
of MeOH was added 1.9 g (9 mmol) of NaIO4. To this mixture
was added 50 mL of water and the solution was stirred at room
temperature for 3 h. The solution was extracted with CH2Cl2,
and the organic extracts were combined, washed with a
saturated NaCl solution, and dried with MgSO4. The solution
was filtered and the solvent was removed under reduced
pressure. The residue was chromatographed on silica gel to
give 1.5 g (72%) of sulfoxide 22 as a pale yellow oil: IR (neat)
1516, 1261, 1235, and 1028 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.34 (t, 3H, J ) 7.6 Hz), 1.62 (d, 3H, J ) 0.8 Hz), 1.76 (d,
3H, J ) 0.8 Hz), 2.75 (t, 2H, J ) 8.4 Hz), 2.71 (m, 1H), 2.97
(m, 1H), 3.60-3.65 (m, 3H), 3.77 (m, 1H), 3.84 (s, 3H), 3.88 (s,
3H), 5.83 (m, 1H), and 6.71-6.78 (m, 3H); 13C NMR (CDCl3,
100 MHz) δ 6.6, 18.1, 22.2, 33.3, 46.5, 49.4, 55.9, 56.1, 111.4,
112.1, 120.9, 132.2, 131.2, 138.4, 147.8, 149.1, and 164.8. Anal.
Calcd for C18H27NO4S: C, 61.16; H, 7.70; N, 3.97. Found: C,
61.04; H, 7.58; N, 4.06.
1389, and 1261 cm-1 1H NMR (300 MHz, CDCl3) δ 1.22 (t,
;
6H, J ) 7.2 Hz), 1.94 (s, 3H), 2.63-2.84 (m, 6H), 3.59 (t, 2H,
J ) 7.6 Hz), 3.83 (s, 3H), 3.86 (s, 3H), 4.86 (s, 1H), 4.98 (s,
1H), 5.09 (s, 1H), 6.76 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
14.2, 20.9, 24.0, 33.4, 47.5, 49.0, 55.8, 111.0, 112.0, 115.8, 120.7,
131.2, 144.2, 147.4, 148.7, and 167.6. Anal. Calcd for C19H29
-
NO3S2: C, 59.51; H, 7.63; N, 3.65. Found: C, 59.36; H, 7.21;
N, 3.60.
2-E t h ylsu lfen yl-8,9-d im et h oxy-10b-m et h yl-1,5,6,10b-
tetr a h yd r o-2H-p yr r olo[2,1-a ]isoqu in olin -3-on e (21). To a
0.25 g (0.7 mmol) sample of enamide 20 in 15 mL of CH2Cl2
at -40 °C was added 0.2 g (1.0 mmol) of dimethyl(methylthio)-
sulfonium tetrafluoroborate (DMTSF).49 The mixture was
stirred for 15 min at -40 °C before warming to 0 °C for 30
min. The reaction mixture was quenched with a saturated
solution of NaHCO3. The organic layer was dried over anhy-
drous MgSO4, the solvent was removed under reduced pres-
sure, and the crude residue was subjected to column chroma-
tography to give 0.17 g (82%) of the title compound as a
2-Eth ylsu lfen yl-8,9-d im eth oxy-1,1-d im eth yl-1,5,6,10b-
tetr a h yd r o-2H-p yr r olo[2,1-a ]isoqu in olin -3-on e (23). To a
mixture containing 1.8 mL (19 mmol) of acetic anhydride, 10
mg of p-TsOH, and 15 mL of toluene was added 0.7 g (1.8
mmol) of sulfoxide 22 in 5 mL of toluene, and the mixture was
heated at reflux for 30 min and then left to stir overnight at
room temperature. The solvent was removed under reduced
pressure and the residue was subjected to silica gel chroma-
tography to give 0.34 g (56%) of 23 as a yellow oil: IR (neat)
1
1689, 1515, 1423, 1255, and 1112 cm-1; H NMR (CDCl3, 400
MHz) δ 0.59 (s, 3H), 1.24 (t, 3H, J ) 7.4 Hz), 1.35 (s, 3H), 2.57
(m, 1H), 2.71-2.83 (m, 4H), 3.03 (s, 1H), 3.79 (s, 3H), 3.82 (s,
(49) Meerwein, H.; Zenner, K.-F.; Gipp, R. J ustus Liebigs Ann.
Chem. 1965, 688, 67.
5934 J . Org. Chem., Vol. 67, No. 17, 2002

Tandem Pummerer/ Mannich Cyclization Cascade
3H), 4.30 (brs, 1H), 4.64 (brs, 1H), and 6.48-6.56 (m, 2H); 13
C
and 172.8. Anal. Calcd for C16H25NOS: C, 68.78; H, 9.03; N,
5.02. Found: C, 68.59; H, 8.87; N, 4.95.
NMR (CDCl3, 100 MHz) δ 14.5, 22.6, 23.1, 25.5, 29.3, 37.1,
44.6, 55.8, 55.9, 56.2, 64.1, 108.5, 112.1, 124.7, 127.7, 147.8,
147.9, 172.3. Anal. Calcd for C18H27NO4S: C, 64.45; H, 7.52;
N, 4.18. Found: C, 64.27; H, 7.44; N, 4.01.
1-Ben zyl-3-et h ylsu lfen yl-7a -m et h yl-2,6-d ioxooct a h y-
d r oin d ole-3a -ca r boxylic Acid Meth yl Ester (35). To a
cooled suspension containing 0.02 g (0.4 mmol) of 34 in 7 mL
of a 1:1 mixture of THF/MeOH was added 0.8 g (6 mmol) of
Na2HPO4 followed by 1.0 g of 5% Na(Hg). The mixture was
stirred at 0 °C for 3 h and then poured into water. The solution
was extracted with chloroform and dried over anhydrous
MgSO4. Silica gel chromatography provided 0.12 g (83%) of
1-benzyl-3-ethylsulfenyl-6-hydroxy-7a-methyl-2-oxooctahydroin-
dole-3a-carboxylic acid methyl ester as a white solid: mp 165-
N-(2-Cycloh ex-1-en yleth yl)-2-eth ylsu lfin yl-N-(2-m eth -
ylp r op en yl)a ceta m id e (24). To 5 mL (44 mmol) of 2-cyclo-
hex-1-enylethylamine at 0 °C was added 4 mL of 2-methyl-
propionaldehyde. The mixture was allowed to stir for 30 min
at 0 °C and then warmed to 25 °C and stirred for an additional
30 min. The solution was dried over Na2SO4, the solvent was
removed under reduced pressure, and the residue was distilled
to give 4.9 g (61%) of (2-cyclohex-1-enylethyl)isobutylidenamine
as a pale yellow oil, which was used in the next step without
further purification: IR (neat) 1671, 1459, 1438, and 1365
1
166 °C; IR (neat) 1738, 1681, 1410, and 1062 cm-1; H NMR
(400 MHz, CDCl3) δ 1.01 (s, 3H), 1.28 (t, 3H, J ) 7.3 Hz), 1.37
(m, 2H), 1.84 (br s, 1H), 1.98-2.21 (m, 4H), 2.70 (q, 2H, J )
7.5 Hz), 3.49 (s, 1H), 3.55 (s, 3H), 3.62 (m, 1H), 4.10 (d, 1H, J
) 15.4 Hz), 4.72 (d, 1H, J ) 15.6 Hz), and 7.23 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 15.2, 21.7, 23.3, 28.5, 30.4, 43.4,
45.9, 50.6, 51.7, 56.9, 63.1, 65.7, 127.2, 127.8, 128.2, 138.3,
171.9 and 172.2. Anal. Calcd. for C20H27NO4S: C, 63.63; H,
7.21; N, 3.71. Found: C, 63.62; H, 7.12; N, 3.69.
1
cm-1; H NMR (CDCl3, 400 MHz) δ 0.99 (d, 6H, J ) 6.8 Hz),
1.52 (m, 4H), 1.91 (m, 4H), 2.13 (t, 2H, J ) 7.2 Hz), 2.35 (m,
1H), 3.35 (t, 2H, J ) 7.2 Hz), 5.34 (brs, 1H), and 7.37 (d, 1H,
J ) 5.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 19.6, 22.7, 23.1,
25.4, 28.7, 34.2, 39.4, 59.8, 122.9, 135.4, and 169.9.
A 1.2 g (8.3 mmol) sample of ethylsulfenyl-acetyl chloride
in 50 mL of CH2Cl2 at 0 °C was added to 1.0 g (5.5 mmol) of
the above imine followed by the addition of 0.5 mL (6.2 mmol)
of pyridine. The reaction mixture was stirred at 0 °C for 30
min, warmed to room temperature, and stirred overnight. The
solvent was removed under reduced pressure and the residue
was chromatographed on silica gel to give 1.3 g (81%) of N-(2-
cyclohex-1-enylethyl)-2-ethylsulfenyl-N-(2-methylpropenyl)ac-
etamide as a yellow oil, which was used in the next step
without purification: IR (neat) 1650 and 1449 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.14 (t, 3H, J ) 7.2 Hz), 1.39-1.49 (m,
4H), 1.51 (d, 3H, J ) 1.2 Hz), 1.63 (d, 3H, J ) 1.2 Hz), 1.83
(m, 4H), 2.01 (t, 2H, J ) 7.2 Hz), 2.53 (q, 2H, J ) 7.2 Hz),
3.06 (s, 2H), 3.39 (t, 2H, J ) 7.2 Hz), 5.31 (brs, 1H), and 5.83
(brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.5, 17.9, 22.0, 22.5,
23.0, 25.4, 26.3, 28.2, 33.4, 35.8, 46.4, 123.0, 124.1, 135.1, 135.7,
and 169.7.
To a solution containing 0.04 g (0.1 mmol) of the above
alcohol in 6 mL of CH2Cl2 was added 0.04 g (0.2 mmol) of
pyridinium chlorochromate. The reaction mixture was stirred
at room temperature for 5 h and the solvent was removed
under reduced pressure. The residue was subjected to silica
gel chromatography to give 0.04 g (97%) of 35 as a colorless
oil: IR (neat) 1730, 1695, 1403, and 1204 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.11 (s, 3H), 1.31 (t, 3H, J ) 7.3 Hz), 2.16
(m, 1H), 2.42 (m, 2H), 2.48 (s, 2H), 2.66 (m, 1H), 2.78 (q, 2H,
J ) 7.3 Hz), 3.48 (s, 1H), 3.66 (s, 3H), 4.25 (d, 1H, J ) 15.4
Hz), 4.60 (d, 1H, J ) 15.6 Hz), and 7.25 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 15.2, 24.0, 28.0, 29.0, 35.9, 43.6, 50.0, 52.0,
52.8, 56.4, 65.1, 127.4, 127.7, 128.4, 137.7, 170.8, 171.7, and
206.5. Anal. Calcd for C20H25NO4S: C, 63.97; H, 6.72; N, 3.73.
Found: C, 63.85; H, 6.71; N, 3.69.
2-Ben zo[1,3]dioxol-5-ylm eth yl-3-[ben zyl(bis(eth ylsu lfe-
n yl)a cetyl)a m in o]bu t-3-en oic Acid Meth yl Ester (37). To
a solution containing 13 g (51 mmol) of 2-benzo[1,3]-dioxol-5-
ylmethyl-3-oxobutyric acid methyl ester47 in 100 mL of toluene
was added 5.6 mL (51 mmol) of benzylamine. The solution was
heated at reflux in a flask equipped with a Dean-Stark trap
for 8 h. The solvent was removed under reduced pressure and
the crude enamide was taken up in 170 mL of CH2Cl2. To this
solution was added 4.6 mL (56 mmol) of pyridine followed by
10 g (51 mmol) of bis(ethylsulfenyl)acetyl chloride.48 The
reaction mixture was stirred at room temperature for 2 h and
was then washed with a saturated NaHCO3 solution. The
organic layer was dried over anhydrous MgSO4. Removal of
the solvent under reduced pressure left a crude oil, which was
purified by silica gel chromatography. The major fraction
contained 16 g (63%) of enamide 37 as a clear oil: IR (neat)
To a 0.9 g (3.4 mmol) sample of the above sulfide in 25 mL
of MeOH was added 1.2 g (5.6 mmol) of NaIO4. Sufficient water
(10 mL) was added to the mixture until it became cloudy and
then the mixture was allowed to stir at 25 °C for 3 h. The
mixture was further diluted with 25 mL of water and extracted
with CH2Cl2. The organic extracts were combined, washed with
a saturated NaCl solution, and dried over MgSO4. The solution
was filtered and the solvent was removed under reduced
pressure. The residue was chromatographed on silica gel to
give 0.7 g (72%) of 24 as a yellow oil: IR (neat) 1643, 1416,
1050, and 1019 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.34 (t,
;
3H, J ) 7.6 Hz), 1.41-1.57 (m, 4H), 1.60 (d, 3H, J ) 1.2 Hz),
1.73 (d, 3H, J ) 1.2 Hz), 1.89-1.93 (m, 4H), 2.08 (t, 2H, J )
7.6 Hz), 2.72-2.78 (m, 1H), 3.01-3.06 (m, 1H), 3.46 (t, 2H, J
) 7.6 Hz), 3.58 (d, 1H, J ) 14 Hz), 3.77 (d, 1H, J ) 14 Hz),
5.37 (brs, 1H), and 5.84 (brs, 1H); 13C NMR (CDCl3, 100 MHz)
δ 6.6, 18.0, 22.2, 22.5, 23.0, 25.5, 28.2, 35.8, 46.3, 46.5, 55.9,
1745, 1645, 1453, and 1204 cm-1 1H NMR (DMSO-d6, 400
;
MHz) δ 1.16 (m, 6H), 2.68 (m, 4H), 2.95 (m, 1H), 2.98 (m, 1H),
3.56 (m, 4H), 4.74 (m, 2H), 4.80 (s, 1H), 5.16 (s, 1H), 5.45 (s,
1H), 5.95 (s, 2H), 6.62 (d, 1H, J ) 8.0 Hz), 6.76 (m, 2H), 7.18
(m, 2H), and 7.28 (m, 3H); 13C NMR (DMSO-d6, 100 MHz) δ
13.8, 13.9, 23.3, 23.5, 36.2, 48.2, 49.1, 51.4, 51.9, 100.6, 107.8,
108.9, 117.8, 121.6, 126.9, 127.6, 128.0, 131.5, 136.9, 143.4,
145.7, 147.1, 167.7, and 171.6. Anal. Calcd for C26H31NO5S2:
C, 62.26; H, 6.23; N, 2.79. Found: C, 66.24; H, 6.08; N, 2.85.
Met h yl 3-E t h ylt h io-15,17-d ioxa -2-oxo-1-b en zylsp ir o-
[p yr r olid in e-5,6′-tr icyclo[7.3.0.03,7]d od eca n e]a -6(7),8(12),-
13-tr ien e-10-ca r boxyla te (38). To a 0.6 g (1.1 mmol) sample
of enamide 37 in 20 mL of CH2Cl2 at -40 °C was added 0.3 g
(1.7 mmol) of DMTSF. The mixture was stirred for 1 h at -40
°C before warming to 0 °C for 30 min. After this time, the
solution was quenched with a saturated NaHCO3 solution and
the aqueous layer was extracted with ether. The combined
organic phase was washed with brine and dried over anhy-
drous MgSO4. The solvent was removed under reduced pres-
sure and the crude residue was crystallized to give 38 as a
123.2, 123.4, 134.9, 137.9, and 164.5. Anal. Calcd for C16H27
-
NO2S: C, 64.61; H, 9.16; N, 4.71. Found: C, 64.55; H, 9.03;
N, 4.66.
2-E t h ylsu lfen yl-1,1-d im et h yl-1,5,7,8,9,10,10a ,10b-oc-
ta h yd r o-2H-p yr r olo[2,1-a ]isoqu in olin -3-on e (25). To a
mixture containing 0.7 mL (6.8 mmol) of acetic anhydride and
10 mg of p-TsOH in 10 mL of toluene at 120 °C was added 0.2
g (0.6 mmol) of sulfoxide 24 in 3 mL of toluene. The resulting
mixture was stirred for 30 min at 120 °C and then the solution
was concentrated under reduced pressure. The residue was
subjected to silica gel chromatography to give 0.09 g (51%) of
25 as a pale yellow oil: IR (neat) 1702 and 1418 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 0.98 (s, 3H), 1.25 (t, 3H, J ) 7.2 Hz), 1.28
(s, 3H), 1.31 (m, 1H), 1.39 (m, 1H), 1.69 (m, 1H), 1.90-2.18
(m, 6H), 2.56 (dd, 1H, J ) 12.8 and 4.0 Hz), 2.76 (t, 2H, J )
9.4 Hz), 2.81 (m, 1H), 3.01 (brs, 1H), 4.09 (brs, 1H), and 5.62
(brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.9, 18.2, 21.2, 25.1,
27.1, 27.3, 27.5, 33.3, 37.7, 41.3, 41.5, 58.8, 70.3, 124.0, 135.4,
J . Org. Chem, Vol. 67, No. 17, 2002 5935

Padwa et al.
white solid: mp 90-91 °C; IR (neat) 1730, 1695, 1247, and
solvent was removed under reduced pressure and the residue
was purified by silica gel chromatography to afford 0.03 g
(72%) of indacene 27, which was identical in every detail with
a sample obtained from the acid-catalyzed reaction of sulfoxide
26.
1
941 cm-1; H NMR (CDCl3, 400 MHz) δ 1.30 (t, 3H, J ) 7.6
Hz), 1.79 (dd, 1H, J ) 14.4 and 10.0 Hz), 2.77-2.91 (m, 4H),
3.08 (dd, 1H, J ) 15.6 and 9.6 Hz), 3.19 (dd, 1H, J ) 9.6 and
8.4 Hz), 3.57 (dd, 1H, J ) 11.2 and 9.6 Hz), 3.63 (s, 3H), 4.09
(d, 1H, J ) 15.2 Hz), 4.74 (d, 1H, J ) 15.2 Hz), 5.92 (s, 1H),
5.96 (s, 1H), 6.35 (s, 1H), 6.62 (s, 1H), and 7.16-7.23 (m, 5H);
13C NMR (CDCl3, 100 MHz) δ 14.3, 25.3, 31.5, 38.6, 41.8, 44.3,
51.2, 51.8, 74.7, 101.4, 103.3, 104.9, 127.3, 128.2, 133.0, 135.7,
4-(1-Ben zen esu lfon yl-1H-in d ol-2-yl)bu tyr a ld eh yd e. To
a solution of 1.8 g (9.4 mmol) of AgBF4 in 25 mL of DMSO
was added 2.8 g (7.3 mmol) of 1-benzenesulfonyl-2-(4-bro-
mobutyl)-1H-indole.50 The reaction mixture was stirred at
room temperature for 18 h and then 1.2 mL (8.7 mmol) of Et3N
was added. After stirring for 20 min, the mixture was diluted
with H2O and extracted with diethyl ether. The combined
organic layers were dried over anhydrous MgSO4, and the
solvent was removed under reduced pressure. The residue was
purified by flash silica gel chromatography to give 1.6 g (69%)
of the titled compound as a white solid: mp 126-128 °C; IR
(KBr) 1724 and 1448 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.09
(q, 2H, J ) 7.4 Hz), 2.53-2.57 (m, 2H), 3.04 (t, 2H, J ) 7.4
Hz), 6.41 (s, 1H), 7.36-7.52 (m, 6H), 7.69-7.72 (m, 2H), 8.15
(d, 1H, J ) 8.2 Hz), and 9.78 (t, 1H, J ) 1.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 21.7, 28.5, 43.3, 109.9, 115.1, 120.5, 123.9,
124.4, 129.9, 133.9, 137.5, 139.0, 141.1, and 202.1. Anal. Calcd
for C18H17O3NS: C, 66.03; H, 5.23; N, 4.28. Found: C, 66.15;
H, 5.06; N, 4.18.
N-[4-(1-Ben zen esu lfon yl-1H -in d ol-2-yl)b u t -1-en yl]-N-
ben zyl-2-eth ylsu lfen yla ceta m id e. To a solution of 0.7 g (2.3
mmol) of the above aldehyde in 10 mL of CH2Cl2 was added
0.3 mL (2.4 mmol) of benzylamine and 1.6 g of anhydrous
MgSO4. The reaction mixture was stirred at room temperature
for 2 h and then filtered. To the filtrate was added 0.5 mL
(5.7 mmol) of pyridine followed by 4.6 mmol of ethylsulfenyl
acetyl chloride. The reaction mixture was stirred at room
temperature for 3 h and then poured into a saturated aqueous
NaHCO3 solution. The aqueous layer was extracted with CH2-
Cl2 and the combined organic layer was washed with a
saturated NH4Cl solution and dried over anhydrous MgSO4.
The solvent was removed under reduced pressure, and the
residue was purified by flash silica gel chromatography to give
0.9 g (80%) of the titled compound as a 2:1 mixture of
inseparable Z/ E isomers: IR (neat) 1641, 1448, 1366, and 686
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.24-1.28 (m, 2H), 2.43-
2.50 (m, 2H), 2.59-2.68 (m, 2H), 2.97-3.01 (m, 2H), 3.26 (s,
2H, minor isomer), 3.43 (s, 2H, major isomer), 4.83 (s, 2H,
major isomer), 4.85 (s, 2H, minor isomer), 4.97-5.05 (m, 1H,
minor isomer), 5.05-5.11 (m, 1H, major isomer), 6.17 (s, 1H,
major isomer), 6.21 (s, 1H, minor isomer), 6.62 (d, 1H, J )
13.7 Hz, major isomer), 7.10-7.52 (m, 11H), 7.65-7.70 (m, 2H),
and 8.12-8.16 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4,
14.5, 26.6, 29.8, 29.9, 30.1, 33.4, 33.8, 47.1, 49.3, 109.7, 110.2,
111.9, 113.7, 115.0, 120.4, 123.08, 123.7, 124.2, 124.3, 125.8,
126.3, 127.0, 127.1, 127.4, 127.6, 128.7, 129.1, 129.4, 129.9,
133.8, 136.3, 137.3, 137.4, 139.1, 139.2, 140.1, 140.8, 168.2,
and 168.3; HRMS calcd for C29H30N2O3S2 518.1698, found
518.1698.
137.6, 147.7, 148.6, 172.4, and 174.5. Anal. Calcd for C24H25
-
NO5S: C, 65.58; H, 5.74; N, 3.19. Found: C, 65.52; H, 5.69;
N, 3.08.
2-Ben zo[1,3]dioxol-5-ylm eth yl-3-[ben zyl(bis(eth ylsu lfe-
n yl)a cetyl)a m in o]bu t-2-en oic Acid Meth yl Ester (39). To
a solution containing 0.65 g (1.3 mmol) of 37 was added 0.4
mL (2.6 mmol) of DBU. The reaction mixture was stirred at
room temperature for 2 h. The solvent was removed under
reduced pressure and the residue was subjected to silica gel
chromatography to separate the 1:1 mixture of stereoisomers.
Compound 39 showed the following properties: IR (neat) 1738,
1709, 1659, 1240, and 1033 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.08 (t, 3H, J ) 7.6 Hz), 1.22 (t, 3H, J ) 7.2 Hz), 2.09 (s,
3H), 2.53-2.85 (m, 4H), 3.48 (s, 3H), 3.58 (s, 2H), 4.58 (d, 1H,
J ) 14.4 Hz), 4.69 (s, 1H), 4.74 (d, 1H, J ) 14.4 Hz), 5.92 (s,
2H), 6.53 (d, 1H, J ) 7.6 Hz), 6.58 (s, 1H), 6.69 (d, 1H, J ) 7.6
Hz), and 7.28 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 14.0, 14.1,
20.0, 22.8, 24.0, 35.3, 50.3, 51.3, 52.2, 100.9, 108.3, 108.6, 121.1,
127.6, 128.3, 129.2, 131.4, 132.1, 136.7, 141.8, 146.2, 147.8,
166.5, and 167.61. Anal. Calcd for C26H31NO5S2: C, 62.26; H,
6.23; N, 2.79. Found: C, 62.07; H, 6.16; N, 2.70.
The isomeric E-alkene 40 exhibited the following spectral
properties: IR (neat) 1723, 1652, 1481, 1247, and 1040 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.26 (t, 3H, J ) 7.6 Hz), 1.29 (t,
3H, J ) 7.2 Hz), 2.06 (s, 3H), 2.71-2.93 (m, 4H), 3.43 (s, 2H),
3.60 (s, 3H), 4.52 (d, 1H, J ) 14.4 Hz), 4.66 (s, 1H), 4.78 (d,
1H, J ) 14.4 Hz), 5.90 (s, 1H), 6.28 (s, 1H), 6.31 (d, 1H, J )
8.0 Hz), 6.62 (d, 1H, J ) 8.0 Hz), 7.28 (m, 4H), and 7.34 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 14.1 20.6, 23.2, 24.1,
35.1, 49.9, 50.0, 51.9, 100.8, 108.0, 108.9, 121.3, 127.8, 128.6,
129.0, 130.9, 133.1, 136.7, 141.5, 146.0, 147.5, 167.7, and 168.2;
HRMS calcd for C26H31NO5S2 501.1644, found 501.1656.
3-Ben zyl-1-eth ylsu lfen yl-3a -m eth yl-2-oxo-2,3,3a ,3b,8a ,9-
h exa h yd r o-1H-5,7-d ioxa -3-a za -cyclop en ta [a ]-s-in d a cen e-
9a -ca r boxylic Acid Meth yl Ester (41). To a 0.12 g (0.2
mmol) sample of enamide 40 in 5 mL of CH2Cl2 was added
0.06 g (0.28 mmol) of DMTSF. The reaction mixture was
stirred at -40 °C for 10 min before warming to room temper-
ature and stirring for an additional 1.5 h. After this time, the
solution was quenched with a saturated solution of NaHCO3
and the aqueous layer was extracted with CH2Cl2. The
combined organic phase was washed with brine and dried over
anhydrous MgSO4. The solvent was removed under reduced
pressure and the crude residue was chromatographed to give
0.07 g (68%) of 41 as a colorless oil: IR (neat) 1723, 1688, 1304,
1
and 1026 cm-1; H NMR (300 Mz, CDCl3) δ 1.23 (s, 3H), 1.37
N-[4-(1-Ben zen esu lfon yl-1H -in d ol-2-yl)b u t -1-en yl]-N-
ben zyl-2-eth a n esu lfin yla ceta m id e (47). To a solution of 0.4
g (0.7 mmol) of the above enamide in 10 mL of a 4:1 mixture
of dioxane and H2O was added 0.6 g (2.7 mmol) of sodium
periodate. The reaction mixture was stirred at room temper-
ature for 12 h, diluted with H2O, and extracted with EtOAc.
The combined organic layers were washed with brine and dried
over anhydrous MgSO4. The solvent was removed under
reduced pressure and the residue was purified by flash silica
gel chromatography to give 0.25 g (68%) of 47 as a 2:1 mixture
(t, 3H, J ) 7.3 Hz), 2.86-2.95 (m, 2H), 3.14 (d, 1H, J ) 16.4
Hz), 3.34 (d, 1H, J ) 16.4 Hz), 3.67 (s, 3H), 4.09 (d, 1H, J )
15.6 Hz), 4.49 (s, 1H), 4.63 (d, 1H, J ) 15.4 Hz), 5.92 (d, 1H,
J ) 1.5 Hz), 5.97 (d, 1H, J ) 1.3 Hz), 6.64 (s, 1H), 6.69 (s,
1H), and 7.11-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
14.8, 19.9, 27.4, 37.4, 43.7, 50.4, 52.7, 64.6, 74.0, 101.4, 104.6,
105.2, 127.1, 127.4, 128.4, 133.6, 136.7, 138.0, 146.7, 148.7,
170.8, and 172.3. Anal. Calcd for C24H25NO5S: C, 65.58; H,
5.74; N, 3.19. Found: C, 65.44; H, 75.78; N, 3.21.
of inseparable Z/ E isomers: IR (neat) 1645 and 1449 cm-1
;
Indacene 27 was also prepared from the DMTSF-induced
reaction of the analogous dithiane 39. To a cooled (-40 °C)
solution containing 0.04 g (0.08 mmol) of dithiane 39 in 2 mL
of CH2Cl2 was added 0.02 g (0.11 mmol) of DMTSF. The
solution was allowed to warm to 0 °C for 2 h before quenching
with a saturated solution of NaHCO3. The aqueous layer was
extracted with CH2Cl2, and the combined organic phases were
washed with brine and dried over anhydrous MgSO4. The
1H NMR (CDCl3, 400 MHz) δ 1.21-1.25 (m, 3H), 2.44-2.56
(m, 2H), 2.72-3.04 (m, 4H), 3.71-3.96 (m, 2H), 4.81 (s, 2H,
major isomer), 4.85 (s, 2H, minor isomer), 5.07-5.15 (m, 1H,
minor isomer), 5.20-5.27 (m, 1H, major isomer), 6.17 (s, 1H,
(50) Padwa, A.; Hertzog, D. L.; Nadler, W. R. J . Org. Chem. 1994,
59, 7072.
5936 J . Org. Chem., Vol. 67, No. 17, 2002

Tandem Pummerer/ Mannich Cyclization Cascade
major isomer), 6.21 (s, 1H, minor isomer), 6.57 (d, 1H, J )
13.8 Hz, major isomer), 7.08-7.52 (m, 11H), 7.66-7.72 (m, 2H),
and 8.14-8.17 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 6.6, 29.4,
29.6, 29.8, 29.9, 46.2, 46.3, 47.9, 49.4, 55.1, 55.2, 110.1, 109.6,
113.2, 114.8, 114.9, 117.5, 120.3, 120.4, 123.7, 123.8, 124.1,
124.2, 125.6, 126.2, 126.6, 127.1, 127.3, 127.7, 127.8, 128.6,
129.1, 129.3, 129.7, 133.7, 133.8, 135.4, 136.3, 137.2, 138.7,
138.9, 140.8, 140.5, 163.7, and 163.8; HRMS calcd for
C29H30N2O4S2 534.1647, found 534.1653.
2.79-3.04 (m, 3H), 3.30 (dd, 1H, J ) 18.6 and 3.6 Hz), 3.36 (s,
1H), 4.02 (d, 1H, J ) 3.6 Hz), 4.80 (1H, J ) 3.6 Hz), and 5.10
(d, 1H, J ) 4.7 Hz), 13C NMR (CDCl3, 100 MHz) δ 14.8, 23.6,
25.1, 25.5, 39.4, 43.8, 48.2, 52.0, 113.8, 114.4, 118.8, 123.7,
124.9, 126.5, 126.6, 127.2, 128.7, 129.6, 129.7, 134.2, 136.3,
137.2, 138.8, 139.1, and 173.1; HRMS calcd for C29H28N2O3S2
516.1541, found 516.1535.
Ack n ow led gm en t. This research was supported by
the National Science Foundation (grant CHE-0132651).
The authors wish to thank Dr. M. Diana Danca for
helpful discussions.
6-Ben zen esu lfon yl-1-ben zyl-3-eth ylsu lfen yl-3,3a ,4,5,6,-
10c-h exa h yd r o-1H-p yr r olo[3,2-c]ca r ba zol-2-on e (48). To
a solution of 0.08 g (0.4 mmol) of trifluoroacetic anhydride in
10 mL of CH2Cl2 was added 0.1 g (0.2 mmol) of 47. The reaction
mixture was stirred at room temperature for 15 min and then
poured into a saturated aqueous NaHCO3 solution. The
aqueous layer was extracted with EtOAc, and the combined
organic layers were dried over anhydrous MgSO4. The solvent
was removed under reduced pressure and the residue was
purified by flash silica gel chromatography to give 0.06 g (60%)
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
experimental procedures for compounds 9, 10, 12, 13, 26-34,
and 42-46. 1H and 13C NMR spectra for new compounds
lacking elemental analyses together with ORTEP drawings for
structures 10, 34, and 38. This material is available free of
charge via the Internet at http://pubs.acs.org.
of 48 as a clear oil: IR (neat) 1688, 1451, 1373, and 1174 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.35-1.39 (t, 3H, J ) 7.4 Hz),
1.81-1.98 (m, 1H), 1.99-2.08 (m, 1H), 2.26-2.35 (m, 1H),
J O020083X
J . Org. Chem, Vol. 67, No. 17, 2002 5937